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US2664428A - delta-17 alpha-hydroxy-3,20-diketo-pregnen-21-als - Google Patents

delta-17 alpha-hydroxy-3,20-diketo-pregnen-21-als Download PDF

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Publication number
US2664428A
US2664428A US243914A US24391451A US2664428A US 2664428 A US2664428 A US 2664428A US 243914 A US243914 A US 243914A US 24391451 A US24391451 A US 24391451A US 2664428 A US2664428 A US 2664428A
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Prior art keywords
diketo
parts
pregnen
hydroxy
volume
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US243914A
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Miescher Karl
Schmidlin Julius
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CIBA PHARM PROD Inc
CIBA PHARMACEUTICAL PRODUCTS Inc
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CIBA PHARM PROD Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J43/00Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J5/00Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general

Definitions

  • a -17/3-hydrox-y-3,20 diketoepregnenemrals. are. already known. In these known aldehydes, the.
  • the A -17a-hydroxy-3,20 diketo.- pregnen-Zlals of the present invention are obtained by reacting anorganic nitroso compound with a quaternary A' -l7a-hydroxy-3,2Q-diketo pregnen-2lyl-ammonium compound, and then liberating the desired aldehyde from the nitrone thus obtained.
  • nitrones such as IliUT benzene and dialk ylam no -nitrosoebenzenes, for example p-dimethylamino-nitroso-benzene.
  • the production of the nitrones takes place in the presence. of an alkaline agent. burprisingly, the condensation may, becarried out in excellent yield even in the presence of a bicarbonate of an alkali metal, as for example potassium bicarbonate.
  • the aldehyde may be liberated by treatment with an acid agent.
  • an acid agent such as pyroracemic acid.
  • Example 1 oil with suction, washed with Example 1 4.90 parts by weight of A -17ahydroxy-3,20.- diketo-pregnen-Zl-yl-pyridinium bromide:
  • a -l7a-hydroxy-3,20 diketo pregnen-Zlyl-pyridinium bromide used as starting material in this example, is prepared for instance as follows:
  • CH2Br are mixed with 7.5 parts by volume of dry pyridine and maintained for 2a hours at room temperature with occasional stirring.
  • the excess of pyridine is then distilled oi as completely as possible under reduced pressure, the formed crystallizate stirred with a parts by volume of methanol and, after 2 hours, the mother liquor filtered with suction followed by washing of the collected crystals with a little ice cold methanol.
  • the pure pyridinium salt is obtained as colorless flat prisms which melt at 285-287 C. (with decomposition and brown diszoloration above 178 C.).
  • the aforementioned Zl-bromo-pregnene itself can be obtained for example by treatment of A B-keto-Zl-bromo pregnadiene with hydrogen peroxide in the presence or" osmium tetroxide.
  • Example 2 21.9 parts by weight of A -1'7a-hydroxy-3,20- diketo-pregnen-2l yl-pyridinium chloride:
  • Example 1 The further working up follows as described in Example 1.
  • the (A -l7a-hydroxy-3-keto-aetiocholenoyl) N (p-dimethylamino phenyl) -nitrone oota.ned is identical with that described in Example 1.
  • a -17a-hydroxy-3,ZO-diketo pregnen-Zlyl-pyridinium chloride used as starting material in this example is prepared, for instance, as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

Patented Dec. 29, 1953 AMu-HYDRQXY-se O-DSIKETO-PREGNEN- 7 Karl Miesclien fihine, and Julius Schmidlin,
. B s witz erlan'd, assignors to Ciba Pharmaceutical ifrod ict s', Ina, Summit, N. J.
- NoDrawing..,Application August 27, 1951,
1' seal-N 243,914 f Claims priority,-application Switzerland September 12.1951) l he present inventionrelatesto A al'laehye droxy-3,-20-diketo-pregnen21-als. and to the preparation thereof. These n elhrhydroxya 3,20-dilreto-pregnen-2l-als may contain addie ticnal free or functionally comerted. hydroxyer keto groups, particularly in the ll-position, orv
may also contain additional doublebonds, asfor example in the 9,11- or 11-,l2-position.
A -17/3-hydrox-y-3,20 diketoepregnenemrals. are. already known. In these known aldehydes, the.
side chain possesses the configuration which results from the reaction of a 1-7-ketonenwith, for example, an organometallic' compound. Compared with these known substances, the pregnenals of the present invention-and especially A l'la-hydroxy 3,20 diketo-pregnen-Zl-al itselfpossess very valuable suprarenal cortex hormone activities. For medical use the new compounds are transformed into tablets or injectable solutions. 1
The A -17a-hydroxy-3,20 diketo.- pregnen-Zlals of the present invention are obtained by reacting anorganic nitroso compound with a quaternary A' -l7a-hydroxy-3,2Q-diketo pregnen-2lyl-ammonium compound, and then liberating the desired aldehyde from the nitrone thus obtained.
As starting materials there are employed espe-. cially quaternary ammonium salts which are derived from heterocyclic basesof aromatic character, such as pyridine, quinoline and isoquinoe line. These startingmaterials are obtained by reaction of the appropriate tertiary amine 'with an ester of the corresponding 2l-hy droxyepregenl a p-Q ad d as e qr a fii d s as a hydrohalio acid or an organic sul fohic acid. Forthe interaction with the quaternary ammonium salt, use is preferably made of a nitroso compound of the aromatic series. suchas IliUT benzene and dialk ylam no -nitrosoebenzenes, for example p-dimethylamino-nitroso-benzene. The production of the nitrones takes place in the presence. of an alkaline agent. burprisingly, the condensation may, becarried out in excellent yield even in the presence of a bicarbonate of an alkali metal, as for example potassium bicarbonate. From the nitrone obtained according to this process, the aldehyde may be liberated by treatment with an acid agent. The same, result is achieved however also by reaction with a carbonyl compound, such as pyroracemic acid.
The following examples illustrate the invention, the relation between parts by Weight and parts by volume being the same as that between the gram and milliliter.
, oil with suction, washed with Example 1 4.90 parts by weight of A -17ahydroxy-3,20.- diketo-pregnen-Zl-yl-pyridinium bromide:
' OH i )3" p6 and 1.55 parts by weight of pnitroso-dimethylaniline are dissolved in parts by volume of methanol with addition oflOO parts by volume of water and mixed with a solution of 1.02 parts by weight of potassium bicarbonate in 50 parts by volume of water. After being kept for 6 days at room temperature'with occasional agitation, the small red plates which have separated are filtered 50 per cent, methanol and then dried. By recrystallization from methylene chloride-methanol, there is obtained the pure (A -l'la-hydroxy-t-keto-aetiocholenoyl)-N(p-dimethylamino-phenyl)-nitrone of the formula:
CH3 CO which melts at 182 C. (with decomposition).
4.80 parts by weight of the thus-obtained (A l'la-hydroxy 3 ketc aetiocholenoyl) -N-(p-dimethylamino-phenyl)-nitrone are covered with 2500 parts by volume of ether and the suspension shaken for 2 hours with 500 parts by volumeof l-normal hydrochloric acid. The aqueous phase is then separated off and the ether solution washed consecutively with l-normal hydrochloric acid, water, 2 percent. sodium bicarbonate solution and water. The aqueous extracts, before being discarded, are extracted several times with ether. The dried ethereal solution is gradually evaporated to about 20 parts by volume whereby in most cases crystallization begins without seeding. The practically colorless substance thus obtained is easily isolated by suction filtration, and is then washed with ether. In this way, there obtained A -l7whydroxy 3,20 diketo-pregnen- 21-al:
CHO
as a hydrate which melts at lO-l08 C. (with decomposition) and which has the rotation [a] =+1l1i2 (C=l.036 in dioxane).
In analogous manner A and A -17ahydroxy-3,20-diketo-pregnadiene-2l-al are prepared.
The A -l7a-hydroxy-3,20 diketo pregnen-Zlyl-pyridinium bromide, used as starting material in this example, is prepared for instance as follows:
1.85 parts by weight of finely powdered A -17ahydroxy-3,20-diketo-2l-bromopregnene:
CH2Br are mixed with 7.5 parts by volume of dry pyridine and maintained for 2a hours at room temperature with occasional stirring. The excess of pyridine is then distilled oi as completely as possible under reduced pressure, the formed crystallizate stirred with a parts by volume of methanol and, after 2 hours, the mother liquor filtered with suction followed by washing of the collected crystals with a little ice cold methanol. By recrystallization from boiling methanol, the pure pyridinium salt is obtained as colorless flat prisms which melt at 285-287 C. (with decomposition and brown diszoloration above 178 C.). The aforementioned Zl-bromo-pregnene itself can be obtained for example by treatment of A B-keto-Zl-bromo pregnadiene with hydrogen peroxide in the presence or" osmium tetroxide.
Example 2 21.9 parts by weight of A -1'7a-hydroxy-3,20- diketo-pregnen-2l yl-pyridinium chloride:
co 1 on water, and the resultant solution admixed with a solution of 4.08 parts by weight of potassium bicarbonate in 200 parts by volume of water. The further working up follows as described in Example 1. The (A -l7a-hydroxy-3-keto-aetiocholenoyl) N (p-dimethylamino phenyl) -nitrone oota.ned is identical with that described in Example 1.
2.40 parts by weight of finely powdered pure (A -l'la-hydroxy 3 -.keto-aetiocholenoyl) -N-(pdimethylamino-phenyl)-nitrone are suspended in 500 parts by volume of ether and shaken with a solution of 8.80 parts by weight of pyroracemic acid in 250 parts by volume of water for 10 days in a nitrogen atmosphere. The ether solution is then separated from the dark red aqueous layer, the latter being further twice extracted with fresh ether before being discarded. The ether solutions are then washed consecutively with water, 2 per cent. sodium carbonate solution and water, then combined and dried with sodium sulfate. By carefully distilling off the ether, there is obtained the A -l7a-hydroxy-3,20-diketo-pregnen-2l-al as the hydrate which melts at 108 C. (with decomposition) as described in Example 1. l
The A -17a-hydroxy-3,ZO-diketo pregnen-Zlyl-pyridinium chloride used as starting material in this example is prepared, for instance, as follows:
6.93 parts by weight of M-l'lazl-dihydroxy- 3,20-diketo-pregnene-(R-eichsteins Substance S) "onion .CHs.. .IQO V I [OH i D are dissolved, with exclusion of moisture, in 50 parts by volume of dry pyridine, 4.80 parts by weight of pure p-tosyl chloride added and, after agitation for a short time, the reaction mixture kept for 12 days in the dark. Then excess pyridine is removed under reduced pressure at room temperature, the formed crystals stirred with 43 parts by volume of acetone and, after several hours standing, the crystals isolated by suction filtration. By recrystallization from methanol, while decolorizing with activated carbon, and by displacing the methanol by means of 96 per cent. ethanol, the pure pyridinium is obtained from the crude salt mixture as colorless platelets which melt at 304-30? C. (with decomposition).
What is claimed is:
l. A A -17a-hydroxy-3,ZO-diketo-pregnen- 21- a1.
2. A -l'la-hydroxy-3,20-diketo-pregnen-2l-al.
KARL MIESCHER. A .aJULIUS SCHMIDLIN.
Name Date Miescher Mar. 10, 1942 Number

Claims (1)

1. A $1-17A-HYDROXY-3,20-DIKETO-PREGNEN-21AL.
US243914A 1950-09-12 1951-08-27 delta-17 alpha-hydroxy-3,20-diketo-pregnen-21-als Expired - Lifetime US2664428A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2920084A (en) * 1956-04-02 1960-01-05 Olin Mathieson 21-nitrones of 9-halo-pregnenes
US2920999A (en) * 1957-06-07 1960-01-12 Pfizer & Co C 21-nitrogen derivatives of corticosteroids
US2951856A (en) * 1954-07-29 1960-09-06 Lab Francais Chimiotherapie Process of dehydrobrominating keto steroids and products obtained thereby
US3022296A (en) * 1956-04-02 1962-02-20 Olin Mathieson Synthesis of steroids

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275790A (en) * 1938-07-01 1942-03-10 Ciba Pharm Prod Inc Aldehydes of the saturated and unsaturated pregnane-series and process of making same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275790A (en) * 1938-07-01 1942-03-10 Ciba Pharm Prod Inc Aldehydes of the saturated and unsaturated pregnane-series and process of making same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2951856A (en) * 1954-07-29 1960-09-06 Lab Francais Chimiotherapie Process of dehydrobrominating keto steroids and products obtained thereby
US2920084A (en) * 1956-04-02 1960-01-05 Olin Mathieson 21-nitrones of 9-halo-pregnenes
US3022296A (en) * 1956-04-02 1962-02-20 Olin Mathieson Synthesis of steroids
US2920999A (en) * 1957-06-07 1960-01-12 Pfizer & Co C 21-nitrogen derivatives of corticosteroids

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